Liposomes have been extensively tested in experimental animals and in humans as a carrier for drugs and nucleic acids. One concern in this use of liposomes is the stability of the liposome during storage and the stability in the blood. The former often limits the clinical use of the liposome and the latter determines the carrier potential of the liposome.
It is well known that liposomes composed of phosphatidylcholine (PC) as the major matrix lipids are generally stable in a simple buffer upon storage and this type of liposome is widely used by many investigators. However, PC-based liposomes rapidly release the entrapped contents upon exposure to serum or plasma, unless cholesterol is included as one of the major lipid components.
Liposomes composed of phosphatidylethanolamine (PE), particularly an unsaturated PE such as dioleoyl PE (DOPE), as the major lipid component have become increasingly important for liposomal drug delivery in recent years. The equilibrium phase of DOPE at physiological temperature and pH is the hexagonal H.sub.II phase. However, the bilayer phase, in the form of liposomes, can be prepared by mixing DOPE with at least one other amphiphile (lipid or protein). These liposomes are generally less stable than the PC-based liposomes upon storage, due to the tendency to revert to the H.sub.II phase. Indeed, special conditions such as acidic pH, or binding with target cells, often trigger a rapid destabilization of the liposomes, making the liposomes suitable for intracellular drug delivery. See, for example Huang et al., U.S. Pat, No. 4,789,633, the disclosure of which is hereby incorporated herein by reference.
Thus, DOPE liposomes stabilized with weakly acidic amphiphiles such as fatty acids, acyl amino acids, and other double-chain lipids, are useful for efficient cytoplasmic delivery of drugs. DOPE liposomes stabilized with acylated antibody, known as target-sensitive immunoliposome, are useful for target-cell surface drug delivery and in vitro diagnosis of virus. See, for example Huang et al., U.S Pat. No. 4,708,933, the disclosure of which is hereby incorporated herein by reference.
At least one such liposome preparation, i.e., large unilamellar liposomes composed of DOPE and oleic acid (OA) (8:2), is not stable in serum, rapid liposome aggregation and content leakage take place within minutes after exposure to serum. Inclusion of cholesterol in such liposomes also improves the liposome stability in serum. Thus, the behavior of the large unilamellar liposomes composed of primarily DOPE is similar to those composed of primarily PC.